The present invention relates to purine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use. In particular the invention relates to 3-substituted and 3,8-disubstituted 6-amino purine derivatives having bronchial and tracheal relaxation and/or anti-inflammatory activity. The invention is also related to the thioisoguanine and dithioxanthine precursor compounds of these purine derivatives, to pharmaceutical compositions containing them and to their medical use.
Cyclic nucleotide phosphodiesterases (PDEs) have received considerable attention as molecular targets for anti-asthmatic agents. Cyclic 3',5'-adenosine monophosphate (cAMP) and cyclic 3',5'-guanosine monophosphate (cGMP) are known second messengers that mediate the functional responses of cells to a multitude of hormones, neurotransmitters and autocoids. At least two therapeutically important effects could result from phosphodiesterase inhibition, and the consequent rise in intracellular cyclic adenosine 3',5'-cyclicmonophosphate (cAMP) or guanosine 3',5'-cyclicmonophosphate (cGMP) in key cells in the pathophysiology of asthma. These are smooth muscle relaxation (resulting in bronchodilation) and anti-inflammatory activity.
It has become known that there are multiple, distinct PDE isoenzymes which differ in their cellular distribution. A variety of inhibitors possessing a marked degree of selectivity for one isoenzyme or the other have been synthesized.
The structure-activity relationships (SAR) of isozyme-selective inhibitors has been discussed in detail, e.g., in the article of Theodore J. Torphy, et al., "Novel Phosphodiesterases Inhibitors For The Therapy Of Asthma", Drug News & Prospectives, 6(4) May 1993, pages 203-214. The PDE enzymes can be grouped into five or more families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. PDE I is stimulated by Ca.sup.2+ /calmodulin. PDE II is cGMP-stimulated, and is found in the heart and adrenals. PDE III is cGMP-inhibited, and possesses positive inotropic activity. PDE IV is cAMP specific, and possesses airway relaxation, antiinflammatory and antidepressant activity. PDE V appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE V inhibitors may have cardiovascular activity.
While there are compounds derived from numerous structure activity relationship studies which provide PDE III inhibition, the number of structural classes of PDE IV inhibitors is relatively limited.
It has previously been shown that the 3,8-disubstituted 6-thioxanthine derivatives as described in EP-A-0256692 exhibit enhanced bronchodilator and anti-inflammatory activity compared to the corresponding xanthine derivatives. Transformation of these 6-thioxanthine derivatives to the corresponding thioisoguanines substantially reduces the bronchodilator and anti-inflammatory activity in certain tests.
PDE IV (and possibly PDE V) is present in all the major inflammatory cells in asthma including eosinophils, neutrophils, T-lymphocytes, macrophages and endothelial cells. Its inhibition causes down regulation of cellular activation and relaxes smooth muscle cells in the trachea and bronchus. On the other hand, inhibition of PDE III, which is present in myocardium, causes an increase in both the force and rate of cardiac contractility. These are undesirable side effects for an anti-inflammatory agent. Theophylline, a non-selective PDE inhibitor, inhibits both PDE III and PDE IV, resulting in both desirable anti-asthmatic effects and undesirable cardiovascular stimulation. With this well-known distinction between PDE isozymes, the opportunity for concomitant anti-inflammation and bronchodilation without many of the side effects associated with theophylline therapy is apparent. The increased incidence of morbidity and mortality due to asthma in many Western countries over the last decade has focused the clinical emphasis on the inflammatory nature of this disease and the benefit of inhaled steroids. Development of an agent that possesses both bronchodilatory and anti-inflammatory properties would be most advantageous. It appears that selective PDE IV inhibitors should be more effective with fewer side effects than theophylline. Clinical support has been shown for this hypothesis. Attempts have therefore been made to find new compounds having more selective and improved PDE IV inhibition.
Surprisingly, the present inventors have found that the analogous transformation of 3 and 3,8-disubstituted thiohypoxanthines, which themselves usually exhibit little if any PDE IV inhibitory activity, to the corresponding purine derivatives gives compounds having PDE IV inhibitory activity comparable to or in some cases greater than 6-thioxanthine derivatives of EP-A-0256692.
A different preparation of 3-methyl-6-dimethylamino-3H-purine, 3-benzyl-6-methylamino-3H-purine and 3-benzyl-6-isopropylamino-3H-purine was reported in J. Org. Chem., 55, 5761-5766 (1990). No biological activity was disclosed for these compounds.